title: Amelioration of beta654-thalassemia in mouse model with the knockdown of aberrantly spliced beta-globin mRNA.
abstract: Large amounts of aberrantly spliced mRNA from the beta(654) allele was present in erythroid cells, which might impair the erythropoiesis. A therapeutic strategy for beta-thalassemia was explored by knocking down the aberrantly spliced mRNA of beta-globin. Lentiviral vector with siRNA fragment targets on the specific portion of beta(654)-globin aberrantly spliced pre-mRNA was constructed. In HeLa beta(654) cells, the siRNA vector could reduce approximately 60% of aberrantly spliced mRNA, which was assessed by RT-PCR and qRT-PCR. Furthermore, a disease model of beta(654) thalassemia mice with lentiviral-mediated siRNA was produced by subzonal injection (named Hbetai-Hbb(th-4)/Hbb(+) transgenic mice). Our results showed that the hemotological parameters were improved in Hbetai-Hbb(th-4)/Hbb(+) transgenic mice. This study provides a potential way for beta(654)-thalassemia therapy by knocking down the aberrantly spliced beta-globin mRNA, whilst supporting that the aberrantly spliced beta-globin mRNA may aggravate the disease.
authors.affiliation: Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Xie
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Ren
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Zhang
authors.forename: Xinbin
authors.initials: X
authors.lastname: Guo
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Huang
authors.forename: Fanyi
authors.initials: F
authors.lastname: Zeng
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Zeng
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055544:beta-Globins